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Light Chain Proteinuria Revealing Mu-Heavy Chain Disease

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Light Chain Proteinuria Revealing Mu-Heavy Chain Disease Case Reports hemolytic anemia, cryoglobulinemia, anti-MAG neu - Light chain proteinuria revealing mu-heavy chain ropathy). Serum-free light chains (sFLC) rarely reach high disease: an atypical presentation of Waldenström levels in WM and complications related to light chains, macroglobulinemia in two cases like nephropathy or amyloidosis, are uncommon 7 com - pared to multiple myeloma. Heavy chain diseases (HCD) are rare mature B-cells We report here two cases with IgM monoclonal gam - 1 κ proliferative disorders first described in 1964 and charac - mopathy visible as a small peak on serum protein elec - terized by the production of a paraprotein consisting of trophoresis (SPEP) and in contrast to a high level of sFLC truncated heavy chains devoid of bound light chains. revealing m-HCD associated with WM. Normal immunoglobulin is composed of two heavy Case 1. In December 2018, a 79 year-old man with chains and two light chains joined by disulfide bonds at chronic renal failure of unknown cause presented with the heavy chain constant domain 1 (CH1). In the absence acute renal failure (creatinine 1,160 mmol/L) associated of light chains, the heat shock protein BiP binds to CH1 with nephrotic syndrome (proteinuria 2,9 g/24 hours and retains the heavy chain in the endoplasmic reticu - and albumin 27 g/L) leading to end-stage renal failure lum. 2 In HCD various mutations are responsible of splic - requiring hemodialysis and normocytic non-regenerative ing error leading to complete or partial deletion of CH1 anemia. The blood count was as following: hemoglobin and preventing therefore the binding of heavy chains to 6 g/dL, platelets 208,000/mm 3, neutrophils 3,100/mm 3, light chains as well as BiP. 3,4 Three HCD involving the lymphocytes 900/mm 3. Kidney biopsy showed intersti - main immunoglobulin (Ig) classes have been described: tial fibrosis and tubular atrophy associated with linear a-HCD, γ-HCD and m-HCD which is the least common. Congo red-negative deposits of κ-light chains along the A single case of d-HCD has been reported. m-HCD is basement membrane suggestive of Randall-type mono - often associated with a B-cell lymphoid disorder such as clonal immunoglobulin deposition disease (MIDD). chronic lymphocytic leukemia with hepatosplenomegaly. sFLC- κ were elevated at 2,585 mg/L with a κ/l ratio of It has also been described in association with myelodys - 57/36. γ globulins were at 6,5 g/L and no peak was plasia, cirrhosis and auto-immune disease. 5 detected on SPEP but immunofixation was positive for Waldenström macroglobulinemia (WM) is a lympho - monoclonal IgM κ (Figure 1A ). Serum immuno-selection plasmacytic lymphoma secreting monoclonal IgM, main - confirmed the presence of m-heavy chain ( m-HC) (Figure ly κ, which is strongly associated with the MYD88 L265P 1B). Bone marrow aspiration and biopsy showed lym - somatic mutation. 6 Patients may be asymptomatic or pho-plasmocytic infiltration with 19% of lymphoid and may present symptoms related either to bone marrow plasma cells on aspiration and 25% of CD19 + CD20 + infiltration and/or to IgM gammopathy physico-chemical cells with monotypic expression of κ-light chain on flow properties (including hyperviscosity, auto-immune cytometry. Immuno-histochemistry on biopsy identified A B C D Figure 1. Immunological tests. On the left side, serum protein electrophoresis and immuno-fixation for patient 1 (A) and patient 2 (C) who had both monoclonal IgM κ. On the right side, immuno-electrophoresis with immuno-selection for patient 1 (B) and patient 2 (D). Black arrow indicate precipitine line consisting of m-heavy chain (continuus arrow for patients, dotted arrow for positive control) 2034 haematologica | 2021; 106(7) Case Reports a monotypic population consisting of 20% of mature hypogammaglobulinemia, elevated sFLC and proteinuria κ + + + plasma cells CD138 and lymphoid cells CD20 CD79a revealing finally m-HCD. The dissociation between the CD5 + CD10 – CD23 –. The screening for L265P mutation sFLC level and the absence of a peak on SPEP was unusu - of MYD88 was positive. No adenomegaly nor splenome - al. Moreover, the presence of vacuolated plasma cells in galia was found on whole-body computed tomography the bone marrow was highly suggestive of m-HCD. In scan. Cardiac markers were increased (troponin 199 ng/L order to detect heavy chains devoid of light chains on and NT-pro BNP 13,664 ng/L) and echocardiography immuno-electrophoresis, immuno-selection techniques suggested infiltrative cardiomyopathy confirmed by car - and the use of specific anti-light chains anti-serum are diac magnetic resonance imaging. Although imaging fea - required. The serum samples were electrophoresed in tures could not distinguish between amyloid and agar containing anti- κ and anti- l antibodies trapping free Randall-type light chain deposition (LCD), endomyocar - lights chains and complete immunoglobulins. The dial biopsy was not performed because of histological throughs contained anti- m antiserum revealing mobile evidence of MIDD in the kidneys. This infiltrative car - free µ-HC through precipitin line (Figure 1B and D). Bone diomyopathy was attributed to probable Randall-type marrow aspiration, immune phenotyping of B cells and LCD. A treatment combining rituximab 375 mg/m² + the presence of monoclonal IgM on immunofixation eas - cyclophosphamide 750 mg/m² + dexamethasone 20 mg ily clarified the diagnosis of WM, in conjunction with the was initiated allowing partial hematological response MYD88 mutation. Of note, this is to our knowledge the after seven cycles. Weekly subcutaneous injections of first report of such a mutation in patients with m-HCD. bortezomib 1.3 mg/m² were then added, leading to a κ/l The association of these two conditions raises the ques - ratio normalization after one cycle of bortezomib, so tion of the underlying pathophysiology and may suggest that cyclophosphamide was discontinued. At date of fol - a continuum between WM and m-HCD: the secretion of low-up in October 2020, the patient had received 13 truncated monoclonal IgM would be secondary to alter - cycles of rituximab and eight courses cycles of borte - ation of immunoglobulin gene within lympho-plasmo - zomib and had achieved a sustained complete hemato - cytic cells. Unfortunately we did not have sufficient bio - logical response. logical sample to perform DNA sequencing. Case 2: In March 2019, a 74 year-old woman presented sFLC are part of the monitoring of multiple myeloma at a rheumatologic clinic for diffuse pains associated with especially oligo-secretory myeloma and light-chain joints swelling leading to the diagnosis of articular chon - myeloma as well as amyloid light-chain amyloidosis. It drocalcinosis. In the context of osteo-articular pains, a has been recently suggested that sFLC could be a reliable SPEP was performed revealing hypogammaglobulinemia marker in WM for prognosis and therapeutic response 10,11 at 2,7 g/L. sFLC- κ were elevated at 3,260 mg/L with a κ/l but currently, the routine use is not recommended in ratio of 14/61. The blood count was as following: hemo - WM. Although m-HCD is a rare condition and renal com - globin 12 g/dL, platelets 374,000/mm 3, neutrophils plications are even more infrequent, it could be cost- 7,660/mm 3, lymphocytes 2,790/mm 3. There was no effective to screen for proteinuria or even to measure hypercalcemia. Urine protein-to-creatinine ratio was at sFLC and light chain proteinuria at diagnosis of lympho - 29 mg/mmol (corresponding to 0,29 g/24 hours of pro - plasmatic lymphoma, especially if the paraprotein is not teinuria) and renal function was normal. Urine protein detected on electrophoresis, because of the possible immuno-electrophoresis revealed Bence Jones protein - harmful renal and systemic consequences of sFLC uria. -2- microglobuline was 2,6 mg/L. Free light chain increase. Indeed, cases of cast nephropathy 12 and sys - β 13 multiple myeloma was suspected and bone marrow aspi - temic amyloidosis associated with m-HCD have been ration was performed which revealed lymphocytic infil - reported and here we described the first case of MIDD. tration consisting of 54% of mature lymphocytes associ - Patient 1 presented Randall-type LCD disease with no ated with 3% plasma cells frequently containing vac - HCD disease. Even though both conditions, HCD disease uoles. This cytologic aspect of low-grade lymphoma was and HCD are due to CH1 deletion, m-HC protein never suggestive of Waldenström disease. Flow cytometry on causes kidney or another organ damage. This difference bone marrow confirmed this diagnosis with a large mon - could be explained by the fact that in -HCD, the CH1 + + + m oclonal κ B-cell population CD19 , CD20 , CD22 , deletion is associated with deletions of a variable region FMC7 +, CD200 +, CD5 –, CD23 –, CD10 –, CD43 –, CD38 –. which seems to be involved in tissue precipitation. L265P mutation of MYD88 was detected. Indeed, it has been reported that sequence analysis of A whole-body computed tomography scan and 18 fluo - HCD disease proteins revealed amino acid substitutions rodeoxyglucose-positron emission tomography scan in the variable region responsible for charge and showed no lytic bone lesion or hepatosplenomegaly or hydrophobicity modifications. 4 lymphadenopathy. Monoclonal IgM κ was detected on Because of the rarety of this condition, there is no serum immunofixation (Figure 1C) and immuno-selec - prospective studies and therefore no guidelines for the tion confirmed the presence of m-HC (Figure 1D). management of m-HCD which is based on case reports. In the absence of clinical impact, no specific treatment In asymptomatic patients such as patient 2, simple mon - was introduced other than sodium bicarbonate to pre - itoring seems reasonable. For symptomatic patients, the vent cast nephropathy. chemotherapy targets the underlying clone as proposed Few cases of -HCD at diagnosis or during the evolu - in the monoclonal gammopathy of clinical significance tion of WM havγe been described 8 and Wahner-Roedler et field.
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